Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to metabolic demands. The generation of these adult endocrine cells predominantly occurs through self-replication rather than through differentiation from their stem-cell progenitors; therefore, regulating cellular division through the cell cycle machinery is an essential component of this process. Arrest of the pancreatic β-cell cycle, which abolishes this replication capability, results in an inability to meet the metabolic demand for insulin, disrupting glucose homeostasis collectively driving type 2 diabetes mellitus-the most common metabolic disease worldwide. Therefore, the purpose of this review is to highlight how upstream cell cycle transcriptional regulators, direct cell cycle modulators, and external stress factors such as DNA damage and genomic instability, influence β-cell replication. We specifically highlight and compare recent animal models created to understand β-cell hyperplasia and hypoplasia as well as offer some insight into potential diabetic therapies.